Intermediates for process for chiral synthesis of 1-β-methyl-carbapenem intermediates

ABSTRACT

A process is described for selectively obtaining 1-β-methylcarbapenem intermediates. The desired chirality is obtained through the hydrogenation of certain bicyclic β-lactam ring structures containing an exocyclic methylene double bond alpha to the β-lactam ring, in the presence of a Group VIII metal hydrogenation catalyst. The hydrogenation results in a mixture of α- and β-methyl epimers having a high β/αepimeric ratio. New 1-β-methylcarbapenem intermediates made by the process are also described.

This is a division of application Ser. No. 703,056, filed Feb. 19, 1985,U.S. Pat. No. 4,617,152.

BACKGROUND OF THE INVENTION

This invention relates to a chiral process for selectively obtaininghigh yields of 1-β-methyl-carbapenem intermediates for the subsequentsynthesis of 1-β-methylcarbapenem antibiotics. The process involvesintroducing an exocyclic α-methylene double bond into a bicyclicβ-lactam ring structure and then subjecting the compound tohydrogenation conditions with a Group VIII transition metalhydrogenation catalyst which preferentially results in the formation ofthe 1-β-methylcarbapenem intermediates.

1-β-Methylcarbapenems, as described in the reference Heterocycles, 1984,Vol. 21, pp. 29-40 by D. H. Shih, F. Baker, L. Cama and B. G.Christensen, are extremely useful and effective broad spectrumantibiotics, useful against a wide variety of bacteria includingGram-positive bacteria including S. aureus, Strep. sp., B. subtilis, andGram-negative bacteria such as E. coli, Shigella sp., Enterobacter sp.,Klebsiella sp., Proteus, Serratia and Pseudomonas sp.

A method of synthesizing 1-β-methylcarbapenems is described in theabove-cited reference in which the beta-methyl chirality is introducedinto the molecule by base-catalyzed alkylation producing a mixture of αand β epimers which are separated by chromatographic procedures.

However, because of the relatively low β/α epimeric ratio obtained bythis alkylation route, newer methods for obtaining the desired β-methylepimer intermediate on a larger scale are constantly being sought.

SUMMARY OF THE INVENTION

It has been found that by introducing an exocyclic α-methylene doublebond into the secondary ring of a bicyclic β-lactam ring system, andthen subjecting said compound to hydrogenation conditions utilizing aGroup VIII transition metal hydrogenation catalyst, the stereochemistryof the molecule enables the hydrogenation to proceed stereoselectivelyto produce the β-methyl isomer in a β/α epimer ratio greater than 1 andas high as 9:1.

In accordance with this invention there is provided a process forstereoselectively reducing an exocyclic methylene double bond in abicyclic compound of the structural formula (I): ##STR1## where R² isindependently H, linear or branched C₁ -C₃ alkyl, which can besubstituted with fluoro or hydroxy, and Y is a divalentbridging-protecting group, derived from a ketone, aldehyde ororganosilicon compound, said group being stable to catalytichydrogenation and removable by acid or base hydrolysis, said processcomprising the step of contacting said compound with a hydrogenatmosphere in the presence of a supported or unsupported Group VIIItransition metal hydrogenation catalyst and in the presence of a solventfor said bicyclic compound, at a temperature below the boiling point ofthe solvent, for a sufficient time to yield a mixture of α- and β-methylepimers having a β/α molar ratio of greater than 1.

The process is illustrated by the following flow diagram: ##STR2##

Further provided is a composition of the following structural formula,being an intermediate useful in producing compositions ofabove-described structure (I): ##STR3## wherein R² is independentlyselected from hydrogen, linear or branched C₁ -C₃ alkyl, which can besubstituted with fluoro, hydroxy, or protected hydroxy, R³ is hydrogenor a protecting group, X is sulfur or selenium, Q is hydroxymethyl,carboxy or C₁ -C₄ alkoxycarbonyl, and R¹ is C₁ -C₄ alkyl, C₆ -C₁₀ aryl,heteroaryl, which can contain substituents inert under the reactionconditions of forming structures I or IV, and include C₁ -C₄ alkyl,alkoxy, nitro and the like.

Furthermore, there is provided a composition of the following structuralformula, an intermediate formed from the oxidation of structure IV and,useful in producing composition (I): ##STR4## wherein R² isindependently selected from hydrogen, linear or branched C₁ -C₃ alkyl,which can be substituted with fluoro, hydroxy, or protected hydroxy, R³is hydrogen or a protecting group, R⁶ is hydrogen, a protecting group,or a covalent bond, and where R⁶ is a covalent bond, R³ and R⁶ arejoined to form Y, a divalent bridging-protecting group derived from aketone, aldehyde or organosilicon compound, said group being stable tocatalytic hydrogenation and removable by acid or base hydrolysis. Asdescribed above, where R³ and R⁶ join to form Y, structure I results.

DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS

The basic invention process is best illustrated by reference to theabove diagram depicting the hydrogenation of structure I.

As is seen, the α-exocyclic methylene double bond of I is hydrogenatedto produce the β-methyl epimer II and the α-methyl epimer III. Thehydrogenation conditions employed are conventional in the art, and itwas found surprisingly that the hydrogenation of structure I,particularly where R² is ##STR5## gave rise selectively to the β-methylepimer in the resulting product mixture which contained a β/α epimermolar ratio of greater than 1.

The catalyst employed in the hydrogenation is a conventional Group VIIItransition metal hydrogenation catalyst typically used for olefins whichcan be soluble or insoluble in the reaction medium, but wherein saidcatalyst is generally not effective for causing hydrogenation of thebicyclic beta-lactam ring structure under the hydrogenation conditions.Preferred metals in the catalyst are nickel, palladium, platinum,rhodium, and the metal in the catalyst can be in the form of free metal,salts or compounds thereof. The catalysts can be used in the bulk andunsupported form, e.g. palladium hydroxide, or in the supported form ona suitable substrate, e.g. activated carbon, inorganic sulfate orcarbonate, said substrate not intervening in the hydrogenation process.Representative examples of Group VIII transition metal hydrogenationcatalysts which can be used include palladium hydroxide, platinum oxide,platinum black, platinum-on-carbon, palladium-on-carbon, colloidalpalladium or platinum, platinum or palladium on barium sulfate or bariumcarbonate, Raney nickel, i.e. W-2, W-4, W-6, or other grades as preparedby conventional procedures, soluble rhodium catalysts including tris(triphenylphosphine) chlororhodium, and the like. The catalyst can besoluble in the solvent used, such as the triphenylphosphine rhodiumcompound, or insoluble, such as the heterogeneous catalysts, eg. RaneyNickel. A preferred catalyst for use in the process is Raney Nickel asproduced by the conventional process described in the reference L. F.Feiser, "Reagents for Organic Synthesis", Vol. 1, p. 723 (John Wiley &Sons, New York), incorporated by reference herein for that purpose.Catalysts operable in the process are produced by conventionalprocedures.

Solvents for Structure I which can be used for the hydrogenation of I inthe process should be inert under the reaction conditions and have aboiling point in the temperature range of about 50°-100° C. for adequatetemperature to be achieved during the process. Representative examplesof solvents which can be used in the process include protic and aproticliquids such as C₁ -C₃ alcohols, C₃ -C₆ alkyl carboxylic esters, C₄cyclic mono- and diethers, and derivatives thereof, which can containsubstituents such as lower alkyl and alkoxy, inert under thehydrogenation conditions. Representative examples include EtOH, MeOH,MeOAc, EtOAc, dioxane, tetrahydrofuran and the like. A preferred solventin the process is EtOH.

Concentrations of I in the solvent can range from 0.001 to 1 molar andpreferably 0.1 to 1 molar.

Temperature employed in the hydrogenation process can range from -78° C.up to the boiling point of the solvent. The preferred temperature rangefor conducting the process is about 0° to 25° C.

Pressure employed in the process can be anywhere from one atmosphere toseveral atmospheres suitable for standard olefin reduction conditions.Preferred is a pressure of about 0-40 psig and particularly about 40psig, containing a substantially hydrogen atmosphere. The hydrogenatmosphere can of course contain other gases which are either reducingor inert under the reaction conditions such as small amounts of carbonmonoxide or carbon dioxide and the like. Preferably the atmosphere usedin the hydrogenation is substantially a hydrogen atmosphere.

The time involved in the hydrogenation is that sufficient under thereaction conditions to obtain substantial catalytic hydrogenation ofstructural formula I to obtain a resulting β/α epimer molar ratio ofgreater than 1. β/α epimer molar ratios of substantially greater than 1are achieved, being generally 1.5 and above and can approach a ratio of9:1 via the hydrogenation step.

The compounds encompassed by structural Formula I include thosecompounds wherein R² is independently selected from H, linear orbranched C₁ -C₃ alkyl, which can be substituted with fluoro, hydroxy orprotected hydroxy. The hydroxy protecting groups included herein areknown in the antibiotic art, are removable by acid or base hydrolysis,and include, inter alia, trialkylsilicon groups such ast-butyldiphenylsilyl, triphenylsilyl, isopropyldimethylsilyl ordimethyl-t-butylsilyl.

A preferred hydroxy protecting silyl group, e.g. t-butyldimethylsilyloxycan be formed by reacting the hydroxy group, e.g. 1-hydroxyethyl, witht-butyldimethylsilyl chloride in a dry solvent such as methylenechloride, DMF, or other inert solvents, in the presence of an acidacceptor, e.g. triethylamine or imidazole, at -20° to 25° C. for aperiod of 1-2 hours and then isolating and purifying the desiredprotected hydroxy compound by conventional methods.

When desired to remove the protecting group, such as prior tohydrogenation, the protected silyloxy can be treated with fluoride, e.g.with tetrabutylammonium fluoride in tetrahydrofuran in dimethylformamidesolvent at room temperature for 1-2 hours. Isolation and purification ofthe resulting hydroxy compound can be accomplished by conventionalprocedures. Generally, in the hydrogenation step of the methylene doublebond, it is preferred to deblock the hydroxy group when present in R²prior to the hydrogenation.

Representative examples of R² include H, CH₃ --, CH₃ CH₂ --, (CH₃)₂CH--, HOCH₂ --, CH₃ CHOH--, CH₃ CH[OSi[C(CH₃)₃ ](CH₃)₂ ]--, (CH₃)₂COH--, FCH₂ --, F₂ CH--, F₃ C--, CH₃ CHF--, CH₃ CF₂ --, (CH₃)₂ CF--, CH₃CH₂ CHOH-- and FCH₂ CHOH--. Preferred is where R² is CH₃ CHOH--.

Y is a bridging-protecting group derived from an aldehyde, ketone ororganosilicon compound, or equivalent thereof, including acetals,ketals, and the like and includes (CH₃)₂ C<, ##STR6## and substitutedderivatives thereof, wherein said substituents are inert during thesubject process described herein and include, inter alia, C₁ -C₄ loweralkyl and alkoxy.

Representative examples of aldehydes, ketones and organosiliconcompounds which are precursors for Y include those which are known inthe antibiotic art, e.g., acetone, 2,2-dimethoxypropane, cyclohexanone,1,1-dimethoxycyclohexane, methylethylketone, 2,2-diethoxy-n-butane,acetaldehyde, acetaldehyde dimethylacetal, acetophenone,p-methoxyacetophenone, dichlorodimethylsilane, dichlorodiphenylsilane,dichloroethylphenylsilane, dichlorodi-t-butylsilane and the like. Apreferred reagent for forming the Y moiety is 2,2-dimethoxypropanewherein the Y moiety is formed by reacting the deblocked amino alcoholof structure V for example with 2,2-dimethoxypropane in the presence ofa catalyst such as boron trifluoride etherate, toluenesulfonic acid, orthe like in a solvent such as methylene chloride, ether, chloroform,dioxane or the like at a temperature of from -10° C. to 35° C. for froma few minutes to 1 hour.

The bridging-protecting group Y, not readily removable by hydrogenation,is removable by acid or base hydrolysis as described in the referenceU.S. Pat. No. 4,234,596, hereby incorporated by reference for thatpurpose.

Structure I is derived as described above from the reaction of ketone,aldehyde or organosilicon compound with the deblocked amino-alcohol V,where R³ and R⁶ are H: ##STR7##

Representative examples of structure I include: ##STR8##

Further examples of Structure I for illustration purposes are givenbelow in the Table indicating specific values chosen for R² andbridging-protecting group Y.

                  TABLE                                                           ______________________________________                                        Compound                                                                              R.sup.2      Y                                                        ______________________________________                                        1       H            (t-Bu).sub.2 Si                                          2       H            Ph.sub.2 Si                                              3       H                                                                                           ##STR9##                                                4       H            (CH.sub.3).sub.2 C                                       5       CH.sub.3     (CH.sub.3).sub.2 C                                       6       CH.sub.3                                                                                    ##STR10##                                               7       CH.sub.3     (CH).sub.3 Si                                            8       CH.sub.3     Ph(CH.sub.3 CH.sub.2)Si                                  9       CH.sub.3 CH.sub.2 CH.sub.2                                                                 Ph(CH.sub.3 CH.sub.2)Si                                  10      CH.sub.3 CH.sub.2 CH.sub.2                                                                 Ph.sub.2 Si                                              11      CH.sub.3 CH.sub.2 CH.sub.2                                                                  ##STR11##                                               12      CH.sub.3 CH.sub.2 CH.sub.2                                                                  ##STR12##                                               13      (CH.sub.3).sub.2 CH                                                                        (CH.sub.3).sub.2 C                                       14      (CH.sub.3).sub.2 CH                                                                         ##STR13##                                               15      (CH.sub.3).sub.2 CH                                                                        (t-Bu).sub.2 Si                                          16      (CH.sub.3).sub.2 CH                                                                        Ph.sub.2 Si                                              17      HOCH.sub.2   Ph.sub.2 Si                                              18      HOCH.sub.2   (CH.sub.3)(CH.sub.3 CH.sub.2)Si                          19      HOCH.sub.2                                                                                  ##STR14##                                               20      HOCH.sub.2   (CH.sub.3).sub.2 C                                       21      (CH.sub.3).sub.2 COH                                                                       (CH.sub.3).sub.2 C                                       22      (CH.sub.3).sub.2 COH                                                                        ##STR15##                                               23      (CH.sub.3).sub.2 COH                                                                       (CH.sub.3).sub.2 Si                                      24      (CH.sub.3).sub.2 COH                                                                       Ph.sub.2 Si                                              25      FCH.sub.2    Ph.sub.2 Si                                              26      FCH.sub.2    (t-Bu).sub.2 Si                                          27      FCH.sub.2                                                                                   ##STR16##                                               28      FCH.sub.2                                                                                   ##STR17##                                               29      F.sub.2 CH                                                                                  ##STR18##                                               30      F.sub.2 CH   (CH.sub.3).sub.2 C                                       31      F.sub.2 CH   Ph.sub.2 Si                                              32      F.sub.2 CH   (t-Bu).sub.2 Si                                          33      F.sub.3 C    (t-Bu).sub.2 Si                                          34      F.sub.3 C    (CH.sub.3).sub.2 Si                                      35      F.sub.3 C                                                                                   ##STR19##                                               36      F.sub.3 C                                                                                   ##STR20##                                               37      (CH.sub.3).sub.2 CF                                                                         ##STR21##                                               38      (CH.sub.3).sub.2 CF                                                                        (CH.sub.3).sub.2 C                                       39      (CH.sub.3).sub.2 CF                                                                        Ph.sub.2 Si                                              40      (CH.sub.3).sub.2 CF                                                                        (CH.sub.3).sub.2 Si                                      ______________________________________                                    

The structures and formulae representative of Structure I given in theabove Table are not meant to be limiting and other combinations of R²and Y and their resulting species of Structure I which will be obviousto one skilled in the art from this disclosure are also deemed to beincluded within the scope of the invention.

A preferred compound of structure I for use in the process is: ##STR22##

A synthesis of a species of general structure I is given below in theFlow Sheet for converting the monocyclic β-lactam ring system into thebicyclic system, 8-oxo-3-oxa-1-azabicyclo[4.2.0]octane with theexocyclic methylene group alpha to the beta lactam ring and a1-hydroxyethyl radical adjacent to the beta lactam carbonyl.

By the same general procedure, the compounds encompassed by Structure I,where R² and Y have other values disclosed herein, within the claimeddefinition, are also obtained. ##STR23##

In words relative to the above Flow Sheet, starting compound A with theindicated stereochemistry where R⁴ is H or t-butyldimethylsilyl, isknown and can be synthesized by the method described in the above-citedHeterocycles reference, hereby incorporated by reference for thisparticular purpose.

The selenation or sulfenylation of A to B is conducted under dry and O₂-free conditions, preferably under nitrogen, by treating A with aproton-abstracting agent such as LDA (lithium diisopropylamide) in ananhydrous solvent such as THF (tetrahydrofuran), and in the presence ofHMPA (hexamethylphosphoramide) to increase rate of reaction, followed bytreating with a selenation or sulfenylation agent. Other protonabstracting agents which can be used are lithium hexamethyldisilazide,NaH, lithium cyclohexylisopropylamide, and the like. Preferred is LDA.Other solvents which can be used in this particular step are glyme,diethylether, dimethylformamide, and the like. The solvent should be dryand inert under the reaction conditions and preferred istetrahydrofuran.

The selenating agent used is a diselenide (or a disulfide ifsulfenylating such as diphenyldisulfide), preferably diphenyldiselenide,and the reaction is carried out at -78° C. to 0° C. under nitrogenatmosphere for a period of time of about 1 to 8 hours to achieve adesired yield of the selenated compound B. The same procedure forsulfenylating can be generally used with the corresponding disulfide. Amixture of alpha and beta selenides is produced, but it is notabsolutely necessary to perform a separation step since eitherdiastereomer or a mixture can be used in the later oxidation step toproduce the methylene compound.

The resulting selenated ester B is hydrolyzed to the acid C byconventional alkaline hydrolysis in e.g., aqueous methanol at atemperature of about 25° to 60° C., for about 2 to 24 hours, under anitrogen atmosphere, to obtain desirable yields of compound C. Othersolvent combinations can also be used, e.g. aqueous ethanol.

The resulting acid C is reduced to the primary alcohol D by a suitablereducing agent, including BH₃.Me₂ S in solvent THF, at a temperature of0° to 65° C., for about 2 to 24 hours under a nitrogen atmosphere toachieve the alcohol. Other reducing agents such as lithium aluminumhydride and borane can also be used which are not detrimental to thebeta-lactam ring.

The alcohol selenide D is then treated with an oxidizing agent such ashydrogen peroxide in acetic acid/THF solvent to form E having theexocyclic double bond at the α-position to the B-lactam ring. Generallythis step is conducted at about 0° to 100° C., for a period of time ofabout 1 to 24 hours. Other oxidizing agents which can be used includem-chloroperbenzoic acid, ozone, and NaIO₄ in solvents includingmethylene chloride, toluene, and EtOH. Preferred oxidizing system ishydrogen perioxide in acetic acid/THF solvent.

Following the above oxidation-elimination procedure, the ring nitrogenis deblocked, if a conventional blocking group is present, by theprocedure of acid or base catalyzed hydrolysis, but not hydrogenation,and the amino alcohol is joined together by reaction with a divalentbridging-protecting group as described herein such as2,2-dimethoxypropane, or the like, in a suitable solvent and presence ofa Lewis acid such as BF₃.Et₂ O, p-toluenesulfonic acid, chlorosulfonicacid to form F. Other bridging-protecting agents which can also be usedare cyclohexanone, p-methoxyacetophenone or its dimethylketal, or adiorganodichlorosilane such as di-t-butyldichlorosilane. Preferred is2,2-dimethoxypropane, reacted in methylene chloride solvent. Followingcyclization the 1'-hydroxy group is deblocked by treating withtetrabutylammonium fluoride in DMF to form G. The deblocking of the1'-hydroxy group has been found to be highly favorable in obtaining ahigh ratio of β/αepimers in the subsequent reduction step.

Following the deblocking step to yield G, the reduction is carried outat described hereinabove with Raney Nickel, to yield a mixture of theβ-methyl and α-methyl epimers H, being H-β and H-α, respectively, withthe β-methyl epimer predominating. The resulting β- and α-isomers can beseparated by high pressure liquid chromatography (HPLC), as for example,on a Pre PAK 500/silica column as in conventional practice or byfractional crystallization or the like to obtain the β-epimer in highpurity.

The β-epimer once obtained in high purity, can be converted to I andthen J by using the methods described in U.S. Pat. No. 4,234,596 herebyincorporated by reference for that purpose.

The reaction H-β→I establishes the blocking group R⁴ and is typicallyaccomplished by treating H-β with a base such as an alkali metalhydroxide, lithium diisopropyl amide, 4-dimethylaminopyridine, orn-butyllithium in a solvent such as methylene chloride, ether, THF,dioxane, DMF, DMSO or the like, followed by treatment with an acylhalide of choice such as an alkanoyl, aralkanoyl or nuclear substitutedaralkanoyl, or alkyl, aryl or aralkyl, substituted aralkyl orsubstituted aryl haloformate such as allylchloroformate orp-nitrobenzylchloroformate or the like at a temperature of from -78° C.to 25° C. for from 1-24 hours.

Alternatively, the protecting group R⁴ may be a triorganosilyl group,such as t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl,isopropyldimethylsilyl, for example, or may be 3,4-dimethoxybenzyl, forexample. Typically R⁴ is established by treating H-β in a solvent suchas CH₂ Cl₂, dimethylformamide, acetonitrile, hexamethylphosphoramide,tetrahydrofuran and the like with a silylating agent such ast-butyldimethylchlorosilane, t-butyldiphenylchlorosilane,triphenylchlorosilane, and the like at a temperature of from -20° to 25°C. for from 0.5 to 24 hours in the presence of a base such astriethylamine, diisopropylethylamine, or imidazole or4-dimethylaminopyridine.

The de-blocking reaction I→J is typically conducted by acid hydrolysissuch as aqueous acetic acid at a temperature of from 25° C. to 75° C.for from 5 minutes to 3 hours.

The oxidation of J to K is accomplished by treating J in a solvent suchas acetone or the like with Jones reagent at from -78° to 25° C. forfrom one minute to 2 hours. Alternatively, the conversions I to J to Kmay be done in one step by treatment of I as above with Jones reagent togive K directly.

The carboxylic acid K can then be be treated for example, by the methoddescribed in the above-cited Heterocycles reference and U.S. Pat. No.4,383,946 and 4,309,346, all hereby incorporated by reference for thispurpose, to arrive at subsequent active 1-β-methylcarbapenemantibiotics, including(-)-(1R,5S,6S)-2-(2-N,N-dimethylamino-2-iminoethylthio)-6-[(1R)-1-hyroxyethyl]-1-methylcarbapen-2-em-3-carboxylicacid, useful as described hereinabove.

Preferred process for selectively reducing an exocyclic α-methylene ringdouble bond of the invention comprises the step of contacting thecompound: ##STR24## in an organic solvent therefor as describedhereinabove, with a hydrogen atmosphere at about 40 psig reactionpressure with Raney nickel catalyst for a time sufficient to obtain amixture of α-methyl and β-methyl epimers in a β to α epimeric molarratio of greater than 1.

Methods of synthesis are given below in the Diagram, Schemes, anddiscussion, for other starting compounds A, where radical R₂ on the betalactam ring is chosen from other groups within the claimed definitiontherefor. The methods are taken from U.S. Pat. No. 4,309,346 and U.S.Pat. No. 4,383,946, which are incorporated by reference specifically forthis purpose. ##STR25##

In words relative to the above diagram, L-aspartic acid 1 is esterifiedaccording to well known procedures. R° is a protecting group such asbenzyl, methyl, ethyl, isopropyl or the like. Typically 1 in a solventsuch as benzene, toluene, chloroform or the like is treated with anesterifying agent such as benzyl alcohol, methanol, ethanol,isopropanol, or the like in the presence of p-toluene sulfonic acid,HCl, HBr, or the like at a temperature of from 0° to 100° C. for from 1to 24 hours to achieve the desired establishment and hence protection ofthe carboxyl functions. The resulting species 2 in a solvent such asether, THF, DME or the like is treated with trimethylchlorosilane, orthe like followed by treatment with EtMgBr, MeMgI, φMgBr, t-BuMgCl, orthe like at a temperature of from -40° to 50° C. for from 1 to 72 hoursto provide azetidinone 3. Reduction of species 3 with a reducing agentsuch as NaBH₄, or the like in a solvent such as methanol, ethanol,isopropanol or the like at a temperature of from -10° to 40° C. for from1 to 6 hours provides 4. (For purposes here, the symbols: Et, Me, φ,iPr, and t-Bu stand for: ethyl, methyl, phenyl, isopropyl, andtert-butyl, respectively.)

Treatment of 4 in a solvent such as methylene chloride, CHCl₃ or thelike with methane sulfonyl chloride, methane sulfonic anhydride or thelike in the presence of a base such as Et₃ N, iPr₂ NEt, or the likefollowed by treatment with a stoichiometric to 5-fold excess of sodiumiodide in acetone yields 5 via 4a.

The transformation 5→6 establishes the protecting group R³ which may bea triorganosilyl group, such as t-butyldimethylsilyl,t-butyldiphenylsilyl, triphenylsilyl, isopropyldimethylsilyl, forexample, or may be 3,4-dimethoxybenzyl, for example. Silyl protection ispreferred, and typically R³ is established by treating 5 in a solventsuch as dimethylformamide, acetonitrile, hexamethylphosphoramide,tetrahydrofuran and the like with a silylating agent such ast-butyldimethylchlorosilane, t-butyldiphenylchlorosilane,triphenylchlorosilane, and the like at a temperature of from -20° to 25°C. for from 0.5 to 24 hours in the presence of a base such astriethylamine, diisopropylethylamine, or imidazole.

The transformation 6→7 is accomplished by treating 6 in a solvent suchas tetrahydrofuran, dimethoxyethane, diethylether or the like with acarbanion generically represented by the following structure: ##STR26##wherein M is a metal cation such as lithium, potassium, copper ormagnesium, for example, and R^(a), R^(b) and R^(c) are selected fromalkyl, aryl or aralkyl such as methyl, ethyl, benzyl, methoxybenzyl,trityl and phenyl, for example, at a temperature of from -100° to 0° C.and from 0.5 to 4 hours.

Typically, the carbanion reagent is prepared prior to addition ofsubstrate 6 on treatment of the triorganothiomethane with a strong basesuch as n-butyllithium, t-butyllithium, phenyllithium, lithiumdiisopropylamide (LDA) or the like.

Resulting intermediate 7 can be mono-, or dialkylated at ring position3. Alkylation of 7 provides 8. Typically, 7 is treated with a strongbase such as lithium diisopropylamide, lithium2,2,6,6-tetramethylpiperidide, potassium hydride, lithiumhexamethyldisilazide, phenyllithium or the like in a solvent such astetrahydrofuran (THF), hexamethylphosphoramide, ether, dimethoxyethane,and the like at a temperature of from -80° C. to 0° C. whereupon thealkylating agent of choice, R² X° is added (X° is chloro, iodo orbromo); alternatively the alkylating agent may be R² -tosylate, R²-mesylate or an aldehyde or ketone such as acetaldehyde to providemonoalkylated species 8.

The eventual 6-substituents (nomenclature relative to final, bicyclicstructure) can also be established by direct acylation using anacylating agent such as N-acyl imidazole or the like. Such N-acylimidazole acylating reagents are listed below. Also given below is adetailed description of this second approach for establishing R².

The following list is representative of useful alkylating agents forestablishing R², according to the above scheme: 7→8 (this will bereferred to as Scheme I, to be distinguished from Scheme II, below,which involves acylation):

ALKYLATING AGENTS

    CH.sub.3 CHO

    CH.sub.2 O

    CH.sub.3 I

    CH.sub.3 COCH.sub.3

    CH.sub.3 CH.sub.2 Br

    (CH.sub.3).sub.2 CHBr

    CH.sub.3 CH.sub.2 CHO

    CF.sub.3 CHO

    CHF.sub.2 CHO

    CH.sub.2 FCHO

    F.sub.2 CHI

    F.sub.3 CI

    CH.sub.3 CF.sub.2 I

The fluoro compounds CH₃ CHF--, and F--CH₂ --, can be prepared from thecorresponding hydroxy compounds by treating the hydroxy compound withDAST™, diethylaminosulfur trifluoride, in an inert solvent such as THF,at a temperature of -78° to 25° C. under an inert atmosphere for aperiod of about 1 to 2 hours. As mentioned above, the 6-substituents mayalso be established by acylation. Utilization of such acylating agentsmay be demonstrated in the following manner with regard to a preferredstarting, or intermediate, material 8. ##STR27##

The alkylation 7→8, is accomplished as previously described, by treating7 in a solvent such as tetrahydrofuran, dimethoxyethane, diethylether,hexamethylphosphoramide, at a temperature of from -100° to -20° C. witha strong base such as lithium diisopropylamide, lithiumhexamethyldisilazide, lithium 2,2,6,6-tetramethylpiperidide, potassiumhydride or the like followed by the addition of an equivalent to 10 foldexcess of an aldehyde. This reaction gives a mixture of isomers fromwhich the desired trans-R form 8 can be conveniently separated by knownmethods of chromatography or crystallization. Intermediate 7 may proceeddirectly to 8 as indicated above, Scheme I, or it may take thecircuitous path via 8'. The direct acylation, to 8' is accomplished bytreating 7 with two or more equivalents of a base such as lithiumdiisopropylamide, lithium hexamethyldisilazide, lithium2,2,6,6-tetramethylpiperidide, in a solvent such as tetrahydrofuran,diethylether, or dimethoxyethane, for example, at a temperature of from-100° to -20° C. with an acylating agent such as N-acyl imidazole or thelike. Addition of the 7 plus base mixture to the acylating agent ispreferred.

Representative acylating agents for this scheme 7→8'→8 are listed below.##STR28##

Further with respect to Scheme II, the reduction 8'→8 is accomplished bycontacting the ketone with a reducing agent such as potassiumtri(sec-butyl)borohydride, lithium tri(sec-butyl) borohydride, sodiumborohydride, sodium tris(methoxyethoxy)aluminum hydride, lithiumaluminum hydride or the like in a solvent such as diethylether,tetrahydrofuran, toluene or the like at a temperature of from -78° to25° C. The reaction can conveniently be conducted in the presence of anadded complexing salt such as potassium iodide, magnesium bromide or thelike.

In a similar manner, unresolved 8 (cis and trans) may be oxidized to 8'for reduction to 8 as indicated above: ##STR29##

The oxidation is accomplished with an oxidizing agent such as dipyridinechromium (VI) oxide, trifluoroaceticanhydride-dimethylsulfoxidetriethylamine, pyridinium dichromate, aceticanhydride-dimethylsulfoxide in a solvent such as methylene chloride,acetonitrile, or the like at a temperature of from -78° to 25° C. forfrom 5 minutes to 5 hours.

Now return to the main scheme of synthesis, Diagram I, and thetransformation 8→9, which is accomplished by treating 8 in a solventsuch as methanol, ethanol, isopropanol, water or the like at atemperature of from 0° to 80° C. with a Lewis acid such as mercuricchloride, silver tetrafluoroborate, thallium trinitrate or the like. Thevalue of R⁵ is determined by the identity of the alcohol taken inreaction.

The triorganylsilyl protecting group R³ may then be removed from 9 togive 10 by treatment with fluoride, e.g. tetrabutylammonium fluoride intetrahydrofuran, in a solvent such as tetrahydrofuran,dimethylformamide, ether or the like at a temperature of from -78° to25° C. for from 1 minute to 2 hours.

The mono-alkylated products 8 through 10, in which R² does not contain achiral center, will exist as a mixture of cis and trans structures:##STR30## the configurational isomerism referring to the 3- and4-hydrogen atoms on the ring. The desired isomer, trans-8 through 10,can be obtained by known methods in the art including crystallizationand chromatography. The resulting trans-10 form can be used directly inproducing the desired 1-betamethyl intermediates, by following theprocedure in Heterocycles, supra, wherein trans-10 is treated with twoequivalents of lithium diisopropylamide (LDA) in THF containing oneequivalent of HMPA (hexamethylphorphoramide) at -78° C. followed byexcess methyl iodide yields a mixture of the alpha and beta methylisomers which is then selenated and carried through the remaining stepsas indicated in the Flow Sheet.

An alternate route for producing the intermediate: ##STR31## where R²=CH₃ CHOH--, is given in U.S. Pat. No. 4,206,219, hereby incorporated byreference for this particular purpose.

Also a subject of the instant invention are the compositions produced inthe above-described process of forming the exocyclic double bond leadingto the desired 1-β-methylcarbapenem intermediates being compositions ofthe Formula: ##STR32## wherein R² is independently selected fromhydrogen, linear or branched C₁ -C₃ alkyl, which can be substituted withfluoro, hydroxy or protected hydroxy, R³ is hydrogen or a protectinggroup, R⁶ is hydrogen, a protecting group, or a covalent bond, and whereR⁶ is a covalent bond, R³ and R⁶ are joined to form Y, a divalentbridging-protecting group, derived from a ketone, aldehyde ororganosilicon compound, said group being stable to catalytichydrogenation and removable by acid or base hydrolysis. The protectinggroups R³ and R⁶ are also removable by acid or base hydrolysis andinclude the triorganosilyl groups known in the art as also representedby R⁴ in Structure A.

The compositions include these wherein said R² is independently selectedfrom H, CH₃ --, CH₃ CH₂ --, (CH₃)₂ CH--, HOCH₂ --, CH₃ CHOH--, (CH₃)₂COH--, FCH₂ --, F₂ CH--, F₃ C--, CH₃ CHF--, CH₃ CF₂, (CH₃)₂ CF--, CH₃CH₂ CHOH--, FCH₂ CHOH--, and wherein said Y includes ##STR33##

Representative Examples of Structure V which include Y through thecoupling of R³ and R⁶ resulting in Structure I are adequatelyillustrated hereinabove and need not be reiterated but are incorporatedby reference herein as supplementing disclosure.

Representative Examples of Structure V where R³ and R⁶ have other valuesthan Y are presented in the following Table:

                  TABLE                                                           ______________________________________                                         ##STR34##                     V                                              Compound R.sup.2           R.sup.3  R.sup.6                                   ______________________________________                                         1       H                 H        H                                          2       CH.sub.3          H        H                                          3       CH.sub.3 CH.sub.2 H        H                                          4       CH.sub.3 CH.sub.2 CH.sub.2                                                                      H        H                                          5       (CH.sub.3).sub.2 CH                                                                             H        H                                          6       HOCH.sub.2        H        H                                          7       CH.sub.3 CHOH     H        H                                          8       (CH.sub.3).sub.2 COH                                                                            H        H                                          9       DMTBSOCH.sub.2    H        H                                         10       DPTBSOCH.sub.2    H        H                                         11       TPSOCH.sub.2      H        H                                         12       IPDMSOCH.sub.2    H        H                                         13       CH.sub.3 CH(ODMTBS)                                                                             H        H                                         14       CH.sub.3 CH(ODPTBS)                                                                             H        H                                         15       CH.sub.3 CH(OTPS) H        H                                         16       CH.sub.3 CH(OIPDMS)                                                                             H        H                                         17       (CH.sub.3).sub.2 C(ODMTBS)                                                                      H        H                                         18       (CH.sub.3).sub.2 C(ODPTBS)                                                                      H        H                                         19       (CH.sub.3).sub.2 C(OTPS)                                                                        H        H                                         20       (CH.sub.3).sub.2 C(OIPDMS)                                                                      H        H                                         21       FCH.sub.2         H        H                                         22       F.sub.2 CH        H        H                                         23       F.sub.3 C         H        H                                         24       CH.sub.3 CHF      H        H                                         25       CH.sub.3 CF.sub.2 H        H                                         26       (CH.sub.3).sub.2 CF                                                                             H        H                                         27       H                 IPDMS    H                                         28       CH.sub.3          IPDMS    H                                         29       CH.sub.3 CH.sub.2 IPDMS    H                                         30       CH.sub.3 CH.sub.2 CH.sub.2                                                                      IPDMS    H                                         31       (CH.sub.3).sub.2 CH                                                                             DMTBS    H                                         32       HOCH.sub.2        DMTBS    H                                         33       CH.sub.3 CHOH     DMTBS    H                                         34       (CH.sub.3).sub.2 COH                                                                            DMTBS    H                                         35       DMTBSOCH.sub.2    DPTBS    DPTBS                                     36       DPTBS-OCH.sub.2   DPTBS    DPTBS                                     37       TPSOCH.sub.2      DPTBS    DPTBS                                     38       IPDMSOCH.sub.2    DPTBS    DPTBS                                     39       CH.sub.3 CH(ODMTBS)                                                                             TBS      H                                         40       CH.sub.3 CH(ODPTBS)                                                                             TPS      IPDMS                                     41       CH.sub.3 CH(OTPS) TPS      DMTBS                                     42       CH.sub.3 CH(OIPDMS)                                                                             TPS      DPTBS                                     43       (CH.sub.3).sub.2 C(ODMTBS)                                                                      H        IPDMS                                     44       (CH.sub.3).sub.2 C(ODPTBS)                                                                      H        DMTBS                                     45       (CH.sub.3).sub.2 C(OTPS)                                                                        H        DPTBS                                     46       (CH.sub.3).sub.2 C(OIPDMS)                                                                      H        TPS                                       47       FCH.sub.2         IPDMS    H                                         48       F.sub.2 CH        IPDMS    H                                         49       F.sub.3 C         IPDMS    H                                         50       CH.sub.3 CHF      DMTBS    H                                         51       CH.sub.3 CF.sub.2 DMTBS    H                                         52       (CH.sub.3).sub.2 CF                                                                             DMTBS    H                                         ______________________________________                                         The abbreviations used:                                                       IPDMS = isopropyldimethylsilyl                                                DMTBS = dimethylt-butylsilyl                                                  DPTBS = diphenylt-butylsilyl                                                  TPS = triphenylsilyl                                                     

The structures and formulas representative of Structure V given in theabove Table are not meant to be limiting, and other combinations of R²,R³ and R⁶ and their resulting species of Structure V, which will beobvious to one skilled in the art in light of this disclosure are alsodeemed to be included within the scope of this invention.

Preferred compositions of Structure V are: ##STR35##

Also a subject of the invention are the intermediate compositions to Iof the Structural formula: ##STR36## wherein R² is describedhereinabove, R³ is hydrogen or a blocking group, X is sulfur orselenium, Q is hydroxymethyl, carboxy or C₁ -C₄ alkoxycarbonyl, and R¹is C₁ -C₄ alkyl, C₆ -C₁₀ aryl, heteroaryl, said aryl and heteroaryl cancontain substituents including C₁ -C₄ alkyl and alkoxy, nitro and thelike, which are inert under the reaction conditions. By the term"substituted phenyl" is meant substituents inert under the reactionconditions leading to the synthesis of structure I and include C₁ -C₄alkyl, alkoxy, nitro and the like.

Representative Examples of Structure IV are given in the followingTable.

    __________________________________________________________________________     ##STR37##                               IV                                   Compound                                                                            R.sup.1                                                                             R.sup.2     R.sup.3                                                                            Q           X                                    __________________________________________________________________________    1     Ph    H           H    HOCH.sub.2  Se                                   2     Ph    CH.sub.3    H    HOCH.sub.2  Se                                   3     Ph    CH.sub.3 CH.sub.2                                                                         H    HOCH.sub.2  Se                                   4     Ph    CH.sub.3 CH.sub.2 CH.sub.2                                                                H    HOCH.sub.2  Se                                   5     Ph    (CH.sub.3).sub.2 CH                                                                       H    HOCH.sub.2  Se                                   6     Ph    HOCH.sub.2  H    HOCH.sub.2  Se                                   7     Ph    CH.sub.3 CHOH                                                                             H    HOCH.sub.2  Se                                   8     Ph    (CH.sub.3).sub.2 COH                                                                      H    HOCH.sub.2  Se                                   9     Ph    FCH.sub.2   H    HOCH.sub.2  Se                                   10    Ph    F.sub.2 CH  H    HOCH.sub.2  Se                                   11    Ph    F.sub.3 C   H    HOCH.sub.2  Se                                   12    Ph    CH.sub.3 CHF                                                                              H    HOCH.sub.2  Se                                   13    Ph    CH.sub.3 CF.sub.2                                                                         H    HOCH.sub.2  Se                                   14    Ph    (CH.sub.3 ).sub.2 CF                                                                      H    HOCH.sub.2  Se                                   15    Ph    DMTBSOCH.sub.2                                                                            H    HOCH.sub.2  Se                                   16    Ph    DPTBSOCH.sub.2                                                                            H    HOCH.sub.2  Se                                   17    Ph    TPSOCH.sub.2                                                                              H    HOCH.sub.2  Se                                   18    Ph    IPDMSOCH.sub.2                                                                            H    HOCH.sub.2  Se                                   19    Ph    CH.sub.3 CH(ODMTBS)                                                                       H    HOCH.sub.2  Se                                   20    Ph    CH.sub.3 CH(ODPTBS)                                                                       H    HOCH.sub.2  Se                                   21    CH.sub.3                                                                            CH.sub.3 CH(OTPS)                                                                         H    HOCH.sub.2  Se                                   22    CH.sub.3                                                                            CH.sub.3 CH(OIPDMS)                                                                       H    HOCH.sub.2  Se                                   23    CH.sub.3                                                                            (CH.sub.3).sub.2 C(ODMTBS)                                                                H    HOCH.sub.2  Se                                   24    CH.sub.3                                                                            (CH.sub.3).sub.2 C(ODPTBS)                                                                H    HOCH.sub.2  Se                                   25    CH.sub.3                                                                            (CH.sub.3).sub.2 C(OTPS)                                                                  H    HOCH.sub.2  Se                                   26    CH.sub.3                                                                            (CH.sub.3).sub.2 C(OIPDMS)                                                                H    HOCH.sub.2  Se                                   27    CH.sub.3                                                                            H           H    COOCH.sub.3 Se                                   28    CH.sub.3                                                                            CH.sub.3    H    COOCH.sub.3 Se                                   29    CH.sub.3                                                                            CH.sub.3 CH.sub.2                                                                         H    COOCH.sub.3 Se                                   30    CH.sub.3                                                                            CH.sub.3 CH.sub.2 CH.sub.2                                                                H    COOCH.sub.3 Se                                   31    CH.sub.3                                                                            (CH.sub.3)CH                                                                              H    COOCH.sub.3 Se                                   32    CH.sub.3                                                                            HOCH.sub.2  H    COOCH.sub.3 Se                                   33    CH.sub.3                                                                            CH.sub.3 CHOH                                                                             H    COOCH.sub.3 Se                                   34    CH.sub.3                                                                            (CH.sub.3).sub.2 COH                                                                      H    COOCH.sub.3 Se                                   35    CH.sub.3                                                                            FCH.sub.2   H    COOCH.sub.3 Se                                   36    CH.sub.3                                                                            F.sub.2 CH  H    COOCH.sub.3 Se                                   37    CH.sub.3                                                                            F.sub.3 C   H    COOCH.sub.3 Se                                   38    CH.sub.3                                                                            CH.sub.3 CHF                                                                              H    COOCH.sub.3 Se                                   39    CH.sub.3                                                                            CH.sub.3 CF.sub.2                                                                         H    COOCH.sub.3 Se                                   40    CH.sub.3                                                                            (CH.sub.3).sub.2 CF                                                                       H    COOCH.sub.3 Se                                   41    4-Pyr DMTBSOCH.sub.2                                                                            H    COOCH.sub.3 Se                                   42    4-Pyr DPTBSOCH.sub.2                                                                            H    COOCH.sub.3 Se                                   43    4-Pyr TPSOCH.sub.2                                                                              H    COOCH.sub.3 Se                                   44    4-Pyr IPDMSOCH.sub.2                                                                            H    COOCH.sub.3 Se                                   45    4-Pyr CH.sub.3 CH(ODMTBS)                                                                       H    COOCH.sub.3 Se                                   46    4-Pyr CH.sub.3 CH(ODPTBS)                                                                       H    COOCH.sub.3 Se                                   47    4-Pyr CH.sub.3 CH(OTPS)                                                                         H    COOCH.sub.3 Se                                   48    4-Pyr CH.sub.3 CH(OIPDMS)                                                                       H    COOCH.sub.3 Se                                   49    4-Pyr (CH.sub.3).sub.2 C(ODMTBS)                                                                H    COOCH.sub.3 Se                                   50    4-Pyr (CH.sub.3).sub.2 C(OTPS)                                                                  H    COOCH.sub.3 Se                                   51    4-Pyr (CH.sub.3).sub.2 C(OIPDMS)                                                                H    COOCH.sub.3 Se                                   52    4-Pyr H           DMTBS                                                                              COOH        Se                                   53    4-Pyr CH.sub.3    DMTBS                                                                              COOH        Se                                   54    p-Tol CH.sub.3 CH.sub.2                                                                         DMTBS                                                                              COOH        Se                                   55    p-Tol CH.sub.3 CH.sub.2 CH.sub.2                                                                DPTBS                                                                              COOCH.sub.2 CH.sub.3                                                                      Se                                   56    p-Tol (CH.sub.3).sub.2 CH                                                                       DPTBS                                                                              COOCH.sub.2 CH.sub.3                                                                      Se                                   57    p-Tol HOCH.sub.2  DPTBS                                                                              COOCH.sub.2 CH.sub.3                                                                      Se                                   58    p-Tol CH.sub.3 CHOH                                                                             TPS  COOCH.sub.2 CH.sub.2 CH.sub.3                                                             S                                    59    p-Tol (CH.sub.3).sub.2 COH                                                                      TPS  COOCH.sub.2 CH.sub.2 CH.sub.3                                                             S                                    60    p-Tol FCH.sub.2   TPS  COOCH.sub.2 CH.sub.2 CH.sub.3                                                             S                                    61    p-Tol F.sub.2 CH  IPDMS                                                                              COOCH(CH.sub.3).sub.2                                                                     S                                    62    p-Tol F.sub.3 C   IPDMS                                                                              COOCH(CH.sub.3).sub.2                                                                     S                                    63    p-Tol CH.sub.3 CHF                                                                              IPDMS                                                                              COOCH(CH.sub.3).sub.2                                                                     S                                    64    p-Tol CH.sub.3 CF.sub.2                                                                         H    COO(CH.sub.2).sub.3 CH.sub.3                                                              S                                    65    p-Tol (CH.sub.3).sub.2 CF                                                                       H    COO(CH.sub.2).sub.3 CH.sub.3                                                              S                                    66    p-MeOPh                                                                             DMTBSOCH.sub.2                                                                            H    COO(CH.sub.2).sub.3 CH.sub.3                                                              S                                    67    p-MeOPh                                                                             DPTBSOCH.sub.2                                                                            H    COOCH.sub.2 CH(CH.sub.3).sub.2                                                            S                                    68    p-MeOPh                                                                             TPSOCH.sub.2                                                                              H    COOCH.sub.2 CH(CH.sub.3).sub.2                                                            S                                    69    p-MeOPh                                                                             IPDMSOCH.sub.2                                                                            H    COOCH.sub.2 CH(CH.sub. 3).sub.2                                                           S                                    70    p-MeOPh                                                                             CH.sub.3 CH(ODMTBS)                                                                       H    COOCH(CH.sub.3)CH.sub.2 CH.sub.3                                                          S                                    71    p-MeOPh                                                                             CH.sub.3 CH(ODPTBS)                                                                       H    COOCH(CH.sub.3)CH.sub.2 CH.sub.3                                                          S                                    72    p-MeOPh                                                                             CH.sub.3 CH(OTPS)                                                                         H    COOCH(CH.sub.3)CH.sub.2 CH.sub.3                                                          S                                    73    p-MeOPh                                                                             CH.sub.3 CH(OIPDMS)                                                                       H    COOC(CH.sub.3).sub.3                                                                      S                                    74    p-MeOPh                                                                             (CH.sub.3).sub.2 C(ODMTBS)                                                                H    COOC(CH.sub.3).sub.3                                                                      S                                    75    p-MeOPh                                                                             (CH.sub.3).sub.2 C(ODPTBS)                                                                H    COOC(CH.sub.3).sub.3                                                                      S                                    76    p-MeOPh                                                                             (CH.sub.3).sub.2 C(OTPS)                                                                  H    COOC(CH.sub.3).sub.3                                                                      S                                    77    p-MeOPh                                                                             (CH.sub.3).sub.2 C(OIPDMS)                                                                H    COOC(CH.sub.3).sub.3                                                                      S                                    __________________________________________________________________________

The abbreviations for the silyl protecting groups DMTBS et al. aredescribed hereinabove and for R¹ include Ph=phenyl, 4-Pyr=4-pyridyl,p-Tol=p-tolyl and p-MeOPh=p-methoxyphenyl.

The structures and formulas representative of Structure IV given in theabove Table are not intended to be limiting, and other combinations ofR¹, R², R³, Q and X and their resulting species of Structure IV, whichwill be obvious to one skilled in the art in light of this disclosureare also deemed to be included within the scope of this invention.

A preferred class of the compositions is of the structural formula:##STR38## wherein R³ and R⁴ are independently hydrogen or a blockinggroup.

Particularly preferred are the compositions of the structural formula:##STR39## wherein R⁵ is H or C₁ -C₄ alkyl, preferably methyl.

A further preferred compound is

The following examples are illustrative of the best mode of carrying outthe invention as contemplated by us and should not be construed to belimitations on the scope or spirit of the instant invention.

EXAMPLE 1 The Stereoselective Preparation of (5R, 6R,7S)-2,2-Dimethyl-7-[(1'R)-1'-Hydroxyethyl]-5-Methyl-8-Oxo-3-Oxa-1-Azabicyclo[4.2.0]Octane##STR41##

At 0° C. under nitrogen, 2.1M n-butyllithium in hexane (9.2 ml, 19.3mmol) is added to a stirred solution of diisopropylamine (2.68 ml, 19.2mmol) in anhydrous tetrahydrofuran (40 ml). The temperature is droppedto -78° C. and hexamethylphosphoramide (3.4 ml) is added. After 5minutes, 1 (2 g, 6.35 mmol) is added in tetrahydrofuran (10 ml), and thereaction mixture is held at -78° C. for 40 minutes. A solution ofdiphenyldiselenide (3.06 g, 9.81 mmol) in tetrahydrofuran (8 ml) isadded. After stirring for 1 hour at -78° C., the reaction mixture ispoured into 1M KH₂ PO₄ (40 ml) H₂ O (400 ml)-Et₂ O (200 ml). The organiclayer is separated, and the aqueous layer is again extracted with Et₂ O(100 ml). The combined ether layers are washed with brine (100 ml),dried over MgSO₄, filtered and concentrated in vacuo to give crude 2(4.75 g). Chromatography on Baker's silica gel (200 g), graduallyeluting with 0% to 50% ethyl acetate in methylene chloride, provides theminor phenylselenyl diastereomer (0.47 g, 16% yield), the majorphenylselenyl diastereomer (1.58 g, 53% yield), and recovered startingmaterial (0.35 g, 18% recovery). Efforts were not made to distinguishbetween the minor and major diastereoisomers as to which was the beta oralpha epimer. The minor diastereomer, or a mixture of diastereomers, canalso be treated to give 5, as indicated below for the major isomer, inSteps B-Step D.

The reported nuclear magnetic resonance (NMR) values herein wereobtained at 200 or 300 MHz in deuterochloroform solvent, usingtetramethylsilane as the internal standard. The values are reported indimensionless delta () units. Abbreviations used include s=singlet,d=doublet, m=multiplet, br. s.=broad singlet. Coupling constants arereported as J.

Infrared (IR) spectroscopic absorption frequencies taken in methylenechloride solvent are reported for specific functional groups in cm⁻¹.

Mass spectrum (ms) data is also presented showing the most abundantmass/charge peak in the spectrum corresponding to the molecular ion (MI)being the molecular weight of the parent, or the trimethylsilyl (TMS)derivative.

Melting points (mp) are presented together with solvent(s) used forrecrystallization.

C, H, N Analyses are reported showing found and theoretical values.

Data for Major Diastereomer 2:

NMR (CDCl₃, TMS): δ 0.04 and 0.08 [2 singlets, Si(CH₃)₂ ], 0.86 [s,SiC(CH₃)₃ ], 1.31 (d, CH₃ CHOSi), 1.53 (s, CH₃ CSe), 3.06 (m, H₃), 3.62(s, OCH₃), 4.22 (d, J=2 Hz, H₄), 4.26 (m, CHOSi), 5.80 (br.s., NH),7.30-7.69 (aromatic protons).

IR (CH₂ Cl₂) 3400 (NH), 1769 (β-lactam C═O), 1725 (ester C═O) cm⁻¹.

mp (recrd. hexane), 115°-118° C.

Anal. calcd. for C₂₁ H₃₃ NO₄ SeSi: C, 53.60; H, 7.07; N, 2.98. Found: C,53.76; H, 7.28; N, 2.87.

Data for Minor Diastereomer 2:

NMR (CDCl₃, TMS): δ 0.07 [s, Si(CH₃)₂ ] 0.87 [s, SiC(CH₃)₃ ] 1.22 (d,CH₃ CHOSi) 1.48 (s, CH₃ CSe) 3.18 (m, H₃) 3.68 (s, OCH₃) 4.00 (d, J=2Hz, H₄) 4.27 (m, CH3CHOSi) 6.05 (br.s, NH) 7.32-7.67 (aromatic protons).

IR (CH₂ Cl₂) 3400 (NH), 1769 (β-lactam C═O), 1725 (ester C═O) cm⁻¹.

mp (recrd. hexane), 128°-130° C.

Anal. calcd. for C₂₁ H₃₃ NO₄ SeSi: C, 53.60; H, 7.07; N, 2.98; Found: C,53.68; H, 7.12; N, 2.91. ##STR42##

To a solution of the major diastereoisomer of 2 (0.89 g, 1.9 mmol) in4:1 MeOH:H₂ O (23 ml), 2.8N NaOH (1.6 ml, 4.5 mmol) is added, and theresultant mixture is heated at 60° C. under nitrogen for 2 hours. Aftercooling to room temperature, the reaction is poured into 2N HCl (5ml)-H₂ O (60 ml)-ethyl acetate (60 ml). After separation of the organicphase, the aqueous layer is again extracted with ethyl acetate (60 ml).The combined organic layers are washed with brine, dried over MgSO4,filtered, and concentrated in vacuo to give crude 3 (0.84 g). The crudematerial is dissolved in chloroform, treated with charcoal, andreconcentrated. Recrystallization of the material from ether provides 3as white crystals (0.43 g, 50% yield). A second crop affords additional3 (0.16 g, 19% yield).

Data for Product of Step B:

NMR (CDCl₃, TMS); δ 0.02 and 0.06 [2 singlets, Si(CH₃)₂ ], 0.86 [s,SiC(CH₃)₃ ], 1.27 (d, CH₃ CHOSi), 1.52 (s, CH₃ CSe), 3.15 (m, H₃), 4.17(d, J=2 Hz, H₄), 4.25 (m, CH₃ CHOSi), 6.31 (NH), 7.31-7.76 (aromaticprotons).

IR (CH₂ Cl₂) 1760 and 1740 (carbonyls) cm⁻¹.

mp (recrd. ether), 172°-176° C.

Anal. Calcd. for C₂₀ H₃₁ NO₄ SeSi: C, 52.62; H, 6.85; N, 3.07; Found: C,52.77; H, 6.82; N, 2.93. ##STR43##

A 10M solution of borane-methylsulfide complex (0.38 ml, 3.8 mmol) isadded to a solution of 3 (0.4 g, 0.88 mmol)) in anhydroustetrahydrofuran at 0° C. under nirogen. After 5 minutes the reactionmixture is allowed to stir at room temperature for 2.5 hours. After thattime period, the reaction is cooled to 0° C. and methanol (4.6 ml) iscarefully added to destroy the excess BH₃. After the initial evolutionof hydrogen, the 0° C. bath is removed, and stirring is continued for 15minutes. The reaction mixture is concentrated in vacuo without heat andthen partitioned between methylene chloride and brine. The organic layeris separated, and the aqueous layer is again extracted with methylenechloride. The combined organic layers are dried over MgSO₄, filtered andconcentrated in vacuo to give crude 4 (0.37 g). Preparative thin layerchromatography on silica gel (eluting with 20% ethyl acetate-methylenechloride and extracting with 10% methanol-methylene chloride) providesthe alcohol, 4 (0.29 g, 75% yield).

Data for Product of Step C:

NMR (CDCl₃, TMS); δ 0.09 and 0.2 [2 singlets, Si(CH₃)₂ ], 0.90 [s,SiC(CH₃)₃ ], 1.26 (s, CH₃ CSe), 1.35 (d, CH₃ CHOSi), 2.76 (dd, CH₂ OH),3.40 (m, H₃), 3.66 (m, CH₂ OH), 3.80 (d, J=2 Hz, H₄), 4.22 (m, CH₃CHOSi), 5.64 (br.s, NH), 7.32-7.74 (aromatic protons).

IR (CH₂ Cl₂) 1760 (β-lactam C═O)cm⁻¹.

mass spectrum (of diTMS derivative) 530 (MI-t-butyl). ##STR44##

To a solution of 4 (0.29 g, 0.65 mmol) in tetrahydrofuran (3.3 ml) at 0°C., acetic acid (0.1 ml, 1.7 mmol) and 30% hydrogen peroxide (0.45 ml,4.0 mmol) are added. After stirring at 0° C. for 5 hours, the reactionmixture is carefully added to cold saturated NaHCO₃ (10 ml) and ether(25 ml). After phase separation, the aqueous layer is again extractedwith ether. The combined ether layers are then washed two times withbrine, dried over MgSO₄, filtered and concentrated in vacuo to crude 5(0.19 g). Preparative thin layer chromatography on silica gel (elutingwith 20% ethylacetate-methylene chloride and extracting with 10%methanol-methylene chloride) provides 5 as a white crystalline product(0.14 g; 78% yield).

Data for Product of Step D:

NMR (CDCl₃, TMS); δ 0.13 [s, Si(CH₃)₂ ], 0.91 [s, SiC(CH₃)₃ ], 1.30 (d,CH₃ CHOSi), 2.30 (m, CH₂ OH), 3.05 (m, H₃), 4.10-4.29 (m, H₄, CH₂ OH andCH₃ CHOSi), 5.20 and 5.23 (2 br s, CH₂ ═C), 6.05 (br s, NH).

IR(CH₂ Cl₂) 1770 (β-lactam C═O)cm⁻¹.

mp-130°-133.5° C.

Anal. Calcd. for C₁₄ H₂₇ NO₃ Si: C, 58.88; H, 9.53; N, 4.91; Found: C,59.08; H, 9.76; N, 4.69. ##STR45##

To a solution of 5 (134 mg, 0.47 m mol) in sieve-dried methylenechloride (3.6 ml) is added 2,2 dimethoxypropane (74 microl., 0.60 mmol)and BF₃.sup.. Et₂ O-(6 microl.). After stirring at room temperatureunder nitrogen for 30 minutes, the reaction mixture is added to 1M K₂HPO₄ (2 ml)-brine (8 ml)-methylene chloride (10 ml). After phaseseparation, the aqueous layer is again extracted with methylene chloride(10 ml). The combined organic layers are washed two times with brine,dried over MgSO₄, filtered and concentrated in vacuo to give crude 6(144 mg). Chromatography on a column of Baker's silica gel eluting with0% to 2% ethyl acetate in methylene chloride provides purified 6 (139mg, 91% yield).

Data for Product of Step E:

NMR (CDCl₃, TMS); δ0.07 and 0.08 [2 singlets, Si(CH₃)₂ ], 0.88 [s,SiC(CH₃)₃ ], 1.25 (d,CH₃ CHOSi), 1.44 and 1.71 [2 singlets, (CH₃)₂ C],3.04 (dd, J=2 and 4 Hz, H₇), 4.16-4.34 (m, H₆, CH₃ CHOSi, and CH₂ O),4.96 and 5.08 (2 br S, CH₂ ═C).

IR (CH₂ Cl₂) 1750 (β-Lactam C═O) cm⁻¹.

mp 46°-48° C.

M.S. 268 (MI-t-butyl), 166 (MI-CH₃ CHOtBDMSi). ##STR46##

To a solution of 6 (67 mg, 0.21 mmol) in anhydrous dimethylformamide at0° C. under nitrogen is added 1M tetrabutylammonium fluoride intetrahydrofuran (0.31 ml, 0.31 mmole), and stirring is continued for 1hour at room temperature. The reaction mixture is added to saturatedaqueous ammonium chloride (20 ml) and ether (20 ml). After phaseseparation, the aqueous phase is again extracted with ether (20 ml). Thecombined ether layers are washed two times with brine, dried, filteredand concentrated in vacuo to give crude 7 (31 mg). Chromatography on asmall column of Baker's silica gel, eluting with 0% to 50% ethyl acetatein methylene chloride, provides purified 7 (26 mg, 60% yield).

Data for Product of Step F:

NMR (CDCl₃, TMS); δ1.33 (d, J=6 Hz, CH₃ CHOH), 1.47 and 1.73 (2singlets, (CH₃)₂ C), 2.62 (br, OH), 3.08 (dd, J=2 and 5 Hz, H₇), and4.22 (m, H₆, CH₃ CHOH, and CH₂ O), 5.05 (center of M, CH₂ ═C)

IR (CH₂ Cl₂) 3650 (OH), 1746 (C═O) cm⁻¹. ##STR47##

Raney Nickel, commercially obtained from W. R. Grace Co., as Grace No.28 Type Raney Nickel (W-4), is washed repeatedly with water until thesupernatant is neutral and then 5 times with ethanol. Six drops of thisRaney Nickel slurry in ethanol is added to 7 (5 mg; 0.024 mmol) inethanol (0.3 ml). The reaction mixture is shaken on a Parr apparatus atroom temperature under 40 p.s.i.g. H₂ for 2.5 hour. The reaction mixtureis then filtered through Celite, rinsing in with ethyl acetate. Thefiltrate is concentrated in vacuo and applied in methylene chloride to asmall column of Baker's silica gel, eluting first with 100% methylenechloride and then 75% ethyl acetate in methylene chloride. The productisolated (4.8 mg, 94% yield) contains a mixture of 8β and 8α in a molarratio of 9:1 as approximated by 300 mHz NMR analysis.

Data for Products of Step G:

NMR (CDCl₃, TMS); δ0.91 (d, α--CH₃), 1.12 (d,β--CH₃), 1.30 (d, CH₃ CHOHof 8β), 1.31 (d, CH₃ CHOH of 8α), 1.42 and 1.74 (2 singlets, (CH₃)₂ C of8β), 1.41 and 1.75 (2 singlets, (CH₃)₂ C of 8α), 1.87 (d, OH), 1.96 (m,H₅), 2.83 (dd, J=2 and 5.5 Hz, H₇ of 8α), 3.06 (dd, J=2 and 6 Hz, H₇ of8β), 3.18 (dd, J=2 and 10 Hz, H₆ of 8α), 3.46 (t, J₄,4 =J₄,5 =12 Hz, H₄of 8α), 3.60 (dd, J₄,4 =12 Hz, J₄,5 =3 Hz, H₄ of 8β), 3.73 (dd, J₄,4 =12Hz, J₄,5 =4.5 Hz, H₄ of 8α), 3.80 (dd, J=2 and 5 Hz, H₆ of 8β), 3.98(dd, J₄,4 =12 Hz, J₄,5 =2 Hz, H₄ of 8β), 4.16 (m, CH₃ CHOH).

MS (of TMS derivative) 285 (MI), 270 (MI--CH₃).

What is claimed is:
 1. A composition of the formula: ##STR48## whereinR² is independently selected from hydrogen, linear or branched C₁ -C₃alkyl, which can be substituted with fluoro, hydroxy or protectedhydroxy, R³ is hydrogen or a protecting group and R⁶ is hydrogen or aprotecting group.
 2. The composition of claim 1 wherein said R² isindependently selected from H, CH₃ --, CH₃ CH₂ --, (CH₃)₂ CH--, HOCH₂--, CH₃ CHOH--, CH₃ CH₂ CHOH--, (CH₃)₂ COH--, FCH₂ CHOH--, FCH₂ --, F₂CH--, F₃ C--, CH₃ CHF--, CH₃ CF₂ -- or (CH₃)₂ CF--.
 3. The compositionof claim 1 the formula: ##STR49## wherein R⁴ is hydrogen or a blockinggroup, and R³ is as previously defined in claim
 1. 4. The composition ofclaim 1 being of the structural formula: ##STR50##